New research may dampen the enthusiasm of anyone looking to extend their lifespan by restricting their caloric intake. Though laboratory rats on calorie-restricted diets can live up to 35 percent longer than their gluttonous counterparts, and previous research on rhesus macaques hinted at modest increases in longevity for dieting primates, data from a long-term prospective study on macaques paints a more nuanced picture.

Published today (August 29) in Nature, research performed at the National Institute on Aging (NIA) suggests that calorie restriction may provide some health benefits, but does not increase lifespan more than a sensible diet.

The finding “is probably an indication that the paradigm for [calorie restriction] work will have to be reshaped,” said William Swindell, a geneticist at the University of Michigan who did not participate in the research.

Increased longevity has been a hallmark of calorie restriction—the reduction of caloric intake by 10 to 40 percent—since the early 20th century, when researchers first began to restrict the diets of laboratory animals, including rats, mice, and nematode worms. More recently, scientists have also focused on health benefits, showing that restraining caloric intake can decrease incidence of type II diabetes and cancer. However, “there were reasons to believe [benefits from lower animals] might not translate to humans,” said NIA researcher Julie Mattison. Monkeys live much longer than lab rats and mice, and in contrast to the much-studied inbred rodents, are genetically diverse, like humans.

In the late 1980s, groups at the University of Wisconsin and the NIA set up two separate studies investigating the effects of long-term calorie restriction on rhesus macaques, whose average lifespan is about 27 years in captivity. The University of Wisconsin group published their 20-year results first, in 2009. After deaths from non-age-related causes, like anesthesia, were removed from analysis, they saw that control monkeys were 3 times more likely to die of age-related causes than calorie restricted (CR) animals. Fewer CR monkeys fell ill with cardiovascular disease, cancer, or diabetes.

In contrast, the newly released NIA results show no difference in mortality between CR and control monkeys. Though reason for these conflicting results remains unclear, one possibility is differences in the CR diets used and variation in the monkeys’ access to food. The Wisconsin group created a diet of mostly purified nutrients, and allowed their control monkeys unrestricted access to food during daylight hours. Not surprisingly, the control group became overweight. NIA, on the other hand, fed their monkeys a diet of mostly whole foods and restricted food access to control monkeys as well, ensuring that they remained at healthy weights.

The Wisconsin study “is more modeling the unfortunate state of obesity,” said Colman, “but if you put the studies together, they’re modeling a pretty broad range [of monkey diets].”

The varied genetics of the monkeys may also be playing a role in the different longevity outcomes seen, said Swindell. A closer look at mouse research suggests that not all mouse strains respond to CR by living longer: some live the same average time, and some actually die earlier, Swindell noted.

Longevity differences aside, the two studies found remarkably similar health benefits of CR monkeys. Both found that monkeys on CR diets were less likely to develop tumors, showed reduced evidence of cardiovascular disease, and had better blood sugar control. Both studies have also found evidence that calorie restriction slows brain aging. The Wisconsin researchers found that age-related brain atrophy is lessened in CR monkeys, while the NIA group previously published that a CR regimen helps prevent symptoms of Parkinson’s disease in macaques.

“I love fact that in a lot of ways what we say really is the same,” said Ricki Colman, first author on the Wisconsin group’s 2009 paper. Colman pointed out that although CR-promoted longevity may get the most attention, possible health benefits are more important. “The point is not to live forever, but live a healthier life,” he said. “That’s what most people are after.”

In the NIA project, however, the researches divided the monkeys into “young-onset” CR macaques, who started caloric restriction between 1 and 14 years old, and “old-onset” CR monkeys, who started CR between 16 and 23 years of age, and found that health benefits depended on the sex and age of CR enrollment. Old-onset male monkeys had lower triglycerides and cholesterol, while young-onset CR monkeys did not show these benefits. When the NIA team looked at cancer, diabetes, arthritis, and cardiovascular disease together, they found no differences between old-onset monkeys and controls; only young-onset CR monkeys seemed to benefit, falling ill later in their lives.

For now, both primate studies will continue, and researchers at NIA and the University of Wisconsin are beginning to collaborate to understand which variables, like diet composition and genetics, are most important in determining CR’s health effects.

Much aging research has “ignored health and focused on longevity,” said Steven Austad of the University of Texas Health Science Center San Antonio, who wrote the Nature commentary on the study but was not involved in the research. The NIA “monkeys got less diabetes and cancer, yet didn’t translate this didn’t translate to longer life,” he said, suggesting that these two effects can—and should—be separated.

“The studies are still ongoing,” Colman noted. “We don’t have the final answers yet.”

"Though reason for these conflicting results remains unclear, one possibility is differences in the CR diets used and variation in the monkeysâ€™ access to food. The Wisconsin group created a diet of mostly purified nutrients, and allowed their control monkeys unrestricted access to food during daylight hours. Not surprisingly, the control group became overweight. NIA, on the other hand, fed their monkeys a diet of mostly whole foods and restricted food access to control monkeys as well, ensuring that they remained at healthy weights." ... The CR monkeys were fed a refined diet, the NIA monkeys were fed whole foods. CR control monkeys became overweight, NIA monkeys did not. Can the two groups be compared in a meaningful way, or is this the more important take away from the study?

Great science and superbly written paper, congrats Julie, Rafa and the rest of the team! Lovely report by The Scientist too. Seems that CR effects on lifespan are not that robust and your data concur with the findings of Jim Nelson's group on CR in recombinant mouse strains.

I am not surprised with this discovery which conflicts a shakydogma. As a matte of fact I haverequested the validity of most experimental researches concluding thelifespan-extending effect by calorie restriction (CR) or dietary restriction(DR). I specifically pointed out that â€œtheconclusions of these studies are often based on the differences in the mediabeing provided but not the amount of food actually consumedâ€쳌 (Experimental Gerontology 45:158-162, 2010; http://www.sciencedirect.com/s.... To overcome this methodological deficiency, Iinvented a new bottle and published â€œA new cultivationsystem for studying chemical effects on the lifespan of the fruit fly(Experimental Gerontology 45:158-162, 2010). The new bottle system allowed long-term cultivation of flies inthe same bottle and thus eliminated the need for transferring of flies betweenvials. Foods/nutrients were provided as fresh moisture medium coated on a glassslide vertically hanged in the center of the bottle. Fly discharges and deadflies were collected onto a draw horizontally inserted into the bottom of thebottle. These features have resulted in great convenience for cultivating fliesand reduced labor and media cost. The effective separation of food fromdischarge may allow accurate mass balance measurement and thus yield moredefinitive observations for understanding the actual role of calorierestriction (CR) or dietary-restriction (DR) in fly metabolism and longevity.

I wish that the future studies on the effects of CR or DR onlongevity will be based on more solid methodologies and comprehensivemeasurements. In that way we may reachsome valid and unified understandings.

Please contact me if you are interested in using the newcultivation system or getting my publications on aging listed at http://im1.biz/Aging.htm by email me at SVL8EPA@gmail.com

If cancer and heart disease age - corrected death rates were less, what DID the CR monkeys die of? To me, this shows the value of death as a measure. IT integrates ALL the bad health. You really cannot claim good health if you die. Now in humans there is the horrid picture of lying in a stainless steel hell being kept alive by iv tubes. That kind of increase in lifespan is NOT desired. But I suspect monkeys were allowed to die without any heroic measures - right? My research is with mice, and when the mice become unresponsive, and show other signs of gross ill health, we do not rush them to the hospital. We humanely euthanize them. Thus with mice at least, lifespan measures the integrated health. Is it the same with these monkeys?

It's not even clear that this study is testing calorierestriction model.

Eating a nutrient dense mash vs eating a restrictedaccess but healthy whole foods diet is not a test of the CR diet. Theessence of the CR diet is calorie restriction: generally about 30% (if Iremember right) less than what would keep you at a normal healthyweight. You are literally hungry all the time. If you don'tintentionally eat only highly nutritious foods, low on calories and high onnutrients, you will be eating too much!

I hate it when bad science is used to disprove interesting and novel hypothesesand it falls by the weigh-side (Freudian slip almost intended).

I believe that the recombinant inbred strains being damaged by CR were NOT given CR - caloric restriction (only "empty" calories restricted). They received DR - diet restriction in which the restricted mice just get less food of a standard diet, in the experiments of Nelson and of Johnson. Most likely when their lifespans decrease due to DR, it is due to the unique combination of deleterious recessives expressed in each of the inbred strains, because they are homozygous at all loci. I suggest that in at least some cases, specific inbred strains require more specific nutrients than available with diet restricted. This is based on personal experience. I published a paper in Nutrition noting that DR in B6 males reduced lifespans, while in B6 females, and both sexes in B6-ob/ob or B6CBAF1, DR with the identical diet increased lifespans. OF course other groups and I tried other diets and we all found some that increased lifespan in B6 males with DR.

The control and CR groups in this study need to be evaluated by BMI (body mass index). The real interesting question is whether high-activity, high-metabolism control animals who have a healthy, lean BMI and less disease live longer. This is what humans who work out a lot and must therefore eat more would like to know.